propylthiouracil and Scleroderma--Systemic

In systemic sclerosis (SSc) vasculopathy affects small arteries and capillaries, but recent evidences show also macrovascular alterations. Experimental data suggest that propylthiouracil (PTU) abrogates the development of cutaneous and pulmonary fibrosis during SSc. The aim of this study was to evaluate the effect of propylthiouracil on aortic lipid peroxidation, intima-media thickness and myofibroblasts differentiation in experimental SSc.. SSc was induced in BALB/c mice by daily subcutaneous injections of hypochlorous acid (HOCl) for 6weeks. Mice (n=25) were randomized to receive daily: HOCl (n=10), HOCl+PTU (n=10), or vehicle (n=5). Thoracic aorta was evaluated by histological methods to measure intima-media thickness and by immunostaining for α-smooth muscle actin (α-SMA) to assess myofibroblast differentiation. Aortic and plasma levels of malondialdehyde (MDA) were also measured.. HOCl induced a significant increase in aortic intima-media thickness compared to controls (p<0.001), while PTU administration prevented intima-media thickening (p<0.01). Myofibroblast differentiation was also less evident in HOCl+PTU-treated animals (p<0.05) compared to mice treated with HOCl alone. The increase in aortic and plasma MDA levels induced by HOCl, was significantly prevented by PTU administration (p<0.05).. PTU, by reducing lipid peroxidation, prevents aortic thickening and myofibroblast differentiation induced by HOCl, reducing macrovascular alterations in experimental SSc.

Topics: Animals; Antithyroid Agents; Aorta, Thoracic; Disease Models, Animal; Female; Lipid Peroxidation; Mice; Mice, Inbred BALB C; Oxidative Stress; Propylthiouracil; Scleroderma, Systemic

Recent advances suggest that the cellular redox state may play a significant role in the progression of fibrosis in systemic sclerosis (SSc). Another, and as yet poorly accounted for, feature of SSc is its overlap with thyroid abnormalities. Previous reports demonstrate that hypothyroidism reduces oxidant stress. The aim of this study was therefore to evaluate the effect of propylthiouracil (PTU), and of the hypothyroidism induced by it, on the development of cutaneous and pulmonary fibrosis in the oxidant stress murine model of SSc.. Chronic oxidant stress SSc was induced in BALB/c mice by daily subcutaneous injections of hypochlorous acid (HOCl) for 6 weeks. Mice (n = 25) were randomized into three arms: HOCl (n = 10), HOCl plus PTU (n = 10) or vehicle alone (n = 5). PTU administration was initiated 30 minutes after HOCl subcutaneous injection and continued daily for 6 weeks. Skin and lung fibrosis were evaluated by histologic methods. Immunohistochemical staining for alpha-smooth muscle actin (α-SMA) in cutaneous and pulmonary tissues was performed to evaluate myofibroblast differentiation. Lung and skin concentrations of vascular endothelial growth factor (VEGF), extracellular signal-related kinase (ERK), rat sarcoma protein (Ras), Ras homolog gene family (Rho), and transforming growth factor (TGF) β were analyzed by Western blot.. Injections of HOCl induced cutaneous and lung fibrosis in BALB/c mice. PTU treatment prevented both dermal and pulmonary fibrosis. Myofibroblast differentiation was also inhibited by PTU in the skin and lung. The increase in cutaneous and pulmonary expression of VEGF, ERK, Ras, and Rho in mice treated with HOCl was significantly prevented in mice co-administered with PTU.. PTU, probably through its direct effect on reactive oxygen species or indirectly through thyroid function inhibition, prevents the development of cutaneous and pulmonary fibrosis by blocking the activation of the Ras-ERK pathway in the oxidant-stress animal model of SSc.

Topics: Actins; Animals; Antithyroid Agents; Blotting, Western; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Female; Fibrosis; Hypochlorous Acid; Hypothyroidism; Immunohistochemistry; Mice; Mice, Inbred BALB C; Muscle, Smooth; Oxidants; Propylthiouracil; Pulmonary Fibrosis; Random Allocation; ras Proteins; Scleroderma, Systemic; Skin; Thyrotropin; Thyroxine; Triiodothyronine; Vascular Endothelial Growth Factor A

Graves' disease (GD) has been reported to be frequently complicated with other autoimmune diseases. However, it is rarely complicated with scleroderma-polymyositis overlap syndrome. Recently, we encountered a 35-year-old woman who developed GD and immune thrombocytopenic purpura during follow-up observation of scleroderma-dermatomyositis overlap syndrome. Platelet counts recovered after high-dose gamma-globulin therapy and bolus methylprednisolone therapy. The present case is the first report of a combination of scleroderma, dermatomyositis, GD, and immune thrombocytopenic purpura. The patient was anti-Ku antibody-positive and had relatively low natural killer T cell counts, both of which might contribute to the complication of multiple autoimmune diseases.

Topics: Adult; Anti-Inflammatory Agents; Antigens, Nuclear; Antithyroid Agents; Autoantibodies; Dermatomyositis; DNA Helicases; DNA-Binding Proteins; Female; Graves Disease; Humans; Ku Autoantigen; Methimazole; Platelet Transfusion; Propylthiouracil; Purpura, Thrombocytopenic, Idiopathic; Scleroderma, Systemic; Steroids